Renal Tubular Reabsorption Research Articles

Visualizing the regulation of SLC34 proteins at the apical membrane.

The cloning of the renal NaPi-2a (SLC34A1) and NaPi-2c (SLC34A3) phosphate transporters has made it possible to characterize the molecular and biophysical regulation of renal proximal tubular reabsorption of inorganic phosphate (Pi). Dietary factors, such as Pi and K, and several hormones and phosphatonins, including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and glucocorticoids, regulate the transporters through various transcriptional, translational, and post-translational mechanisms that involve acute trafficking via endocytosis or exocytosis, interactions with PDZ domain proteins, lipid microdomains, and diffusion and clustering in the apical brush border membrane. The visualization of these trafficking events by means of novel microscopy techniques that includes fluorescence lifetime imaging microscopy (FLIM), Förster resonance energy transfer (FRET), fluctuation correlation spectroscopy (FCS), and modulation tracking (MT), is the primary focus of this review.

Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Polymyxins: Implications for Therapeutic Use.

The availability of sensitive, accurate and specific analytical methods for the measurement of polymyxins in biological fluids has enabled an understanding of the pharmacokinetics of these important antibiotics in healthy humans and patients. Colistin is administered as its inactive prodrug colistin methanesulfonate (CMS) and has especially complex pharmacokinetics. CMS undergoes conversion in vivo to the active entity colistin, but the rate of conversion varies from brand to brand and possibly from batch to batch. The extent of conversion is generally quite low and depends on the relative magnitudes of the conversion clearance and other clearance pathways for CMS of which renal excretion is a major component. Formed colistin in the systemic circulation undergoes very extensive tubular reabsorption; the same mechanism operates for polymyxin B which is administered in its active form. The extensive renal tubular reabsorption undoubtedly contributes to the propensity for the polymyxins to cause nephrotoxicity. While there are some aspects of pharmacokinetic behaviour that are similar between the two clinically used polymyxins, there are also substantial differences. In this chapter, the pharmacokinetics of colistin, administered as CMS, and polymyxin B are reviewed, and the therapeutic implications are discussed.

OR-020 High-intensitive training leads to increasing apoptosis of podocyte in kidneys of rats

Objective Athletes often choose high-intensitive training load to improve athletic ability in their training cycle, its purpose is to pursue the super-compensation after training, but athletes and coaches frequently ignore the balance between load and reasonable recovery, which produce a sustained decline in athletic ability and physical function, and cause the viscera function disorder. High-intensitive training damages the structure of renal filtration barrier in rats, especially the destruction and fracture of Silt diaphragm ultrastructure, as well as the partial fusion of foot processes, etc., so that the large amount of macromolecular proteins in the blood leak out far beyond the threshold of renal tubular reabsorption and form exercise-induced proteinuria. Podocyte is one of the most important. This research establishes a model of rats which simulates the progressive-load training in the cycle of athletes. Observe the apoptosis of renal cells in rats by bioimaging. Determine whether long-term intensive training causes apoptosis in kidney of rats or podocytes, and detect the expression and distribution of Bcl-2 and Bax, and the protein expression of Caspase-3, which is the final regulatory factor of apoptosis pathway. Study the mechanism of the abnormal podocyte due to intensive training from the characterization of kidney to the molecular level, providing experimental basis for explaining the relationship between intensive-training and exercise-induced proteinuria to guide of scientific training. Methods This study selects 36 Sprague-Dawley rats, which are randomly divided into 3 groups: a control group (group C, 12), a group drawn immediately after exercise(group EI, 12), a group drawn 24 h after exercise(group EA, 12). Group C does not train. The rats in group EI and EA train on the treadmill with an increasing load for 6 weeks(10% grade, 6 d/w): in the first week, the rats run for 10 min at 10 m/min. Starting from the second week, the running speed increases by 5m/min/w, and the training time increases by 30min/w. In the last week the rats run to exhaustion if they could not maintain the target intensity. Record the exhausting time of rats, then group EI and group EA are respectively drawn immediately and 24 hours after exercise. Detect the apoptosis of renal cell apoptosis in rats by TUNEL, observe the ultrastructure of podocytes by TEM, detect urine total protein by BCA, serum and urine creatinine by Jaffe, serum urea by two-point dynamic method, the expression and distribution of Bcl-2 and Bax by immunohistochemistry, and the expression of Caspase-3 by western-blot. Results The rats in group EI and EA gradually lose weight at the first weekend of training, and their weight drop significantly from the third weekend to the end, it shows a significant difference compared with group C(p 0.05), while group EA is higher than group C and EI(p<0.05). Conclusions Persistent proteinuria is observed in rats after intensitive training, their renal function is disordered and cannot be effectively recovered after 24 h rest, and renal cell apoptosis increases. High-intensitive training reduces the expression of Bcl-2, and the Bax/Bcl-2 ratio increases with the prolongation of recovery time. Caspase-3 shows the same trend. It is suggested that the change in the expression and ratio of Bax and Bcl-2 in renal under excessive training stress is an important regulatory mechanism for the occurrence of apoptosis in renal cells. Meanwhile the apoptosis of renal cells increases in rats after training, and the apoptosis characteristics of podocyte in the glomerulus are obvious at 30 min and 24 h after exercise, and the structure and function of Slit diaphragm are damaged.

Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy

Congenital hypophosphataemia (CH) is a collection of disorders that cause defective bone mineralisation manifesting with rickets in childhood and osteomalacia in adulthood. Bone turnover markers (BTMs) are surrogate measures of metabolic bone disease severity. We explored the utility of BTMs in 27 adults with CH: 23 had X-linked hypophosphataemia (XLH), of whom 2 were hypoparathyroid post-total parathyroidectomy (PTx); 2 had autosomal dominant hypophosphataemic rickets (ADHR), and 2 had none of the known mutations. We measured the renal tubular maximum reabsorption rate of phosphate (TmP/GFR), C-terminal fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), ionised calcium, 1,25-dihydroxyvitamin D [1,25(OH)2D], and a panel of BTMs: serum bone-specific alkaline phosphatase (bone ALP), osteocalcin (Oc), total procollagen type I amino-terminal propeptide (PINP), and carboxy-terminal telopeptide of type I collagen (CTX); and urine amino-terminal telopeptides of type I collagen (uNTX). After excluding 2 patients with XLH and PTx, the frequency of abnormal elevation in BTMs was: bone ALP (96%); CTX (72%); PINP (52%); uNTX (48%); Oc (28%). The strongest association with bone ALP was TmP/GFR. Those patients receiving phosphate supplements and alfacalcidol had significant elevation in CTX. The 2 patients with XLH and PTx had normalisation of TmP/GFR and near normalisation of BTMs post-operatively, despite marked elevation in both C-terminal and intact FGF23. In conclusion, BTMs in our CH patients indicated that most have abnormalities consistent with osteomalacia and many have mild secondary hyperparathyroidism; and the normalisation of TmP/GFR after total PTx in 2 cases of XLH remains unexplained, but possible causes are speculated.

Phosphate wasting disorders in adults

A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.

Burosumab Therapy in Children with X-Linked Hypophosphatemia

BackgroundX-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia.MethodsIn an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events.ResultsThe mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity.ConclusionsIn children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577; EudraCT number, 2014-000406-35).

Renal function and integrity are preserved when hydroxyethyl starch is dosed to acutely restore blood pressure after blood loss in rats

Hydroxyethyl starch (HES) is used clinically to replace blood loss and stabilize hemodynamics. However, the functional consequences on the kidney have not been fully investigated. Here we determine whether a single application of hydroxyethyl starch, dosed to restore blood pressure (BP) within minutes following a blood loss, affects kidney outcome when assessed one day or one week later.MethodsUnder short‐term anesthesia, Sprague‐Dawley rats were subjected to a 25% blood loss over 6.25 min via the femoral vein. Immediately thereafter, the Volulyte® 6% containing HES 130/0.4 (VOL) or Hextend® 6% containing HES 670/0.7 (HEX) or a balanced crystalloid solution (Isolyte®, ISO) were infused i.v. to restore BP within 4–4.5 minutes. Pilot studies established that this required doubling of the infused volume of ISO (20ml/kg) vs VOL and HEX (each 10ml/kg). Sham operated rats without blood loss/volume substitution were used as control (CON). Renal function was determined in renal clearance studies (using 3H‐inulin and paramino hippurate [PAH]) under terminal anesthesia. In separate groups of animals plasma and urine were collected and kidneys harvested for gene expression analysis. N=10–11/group.ResultsAs expected, hematocrit was significantly lower at 1 day after hemorrhage versus CON. The initial hematocrit drop at day 1 and the subsequent recovery after 1 week were similar in ISO, VOL and HEX. As indicated by similar values for body weight, blood pressure, plasma electrolytes, and hormone markers (including renin, ANP and ADH) among the 4 groups, the 3 volume substitution protocols rapidly restored the volume status at 1 day after hemorrhage and this effect was sustained 1 week later. The data also indicated that ISO, VOL and HEX similarly preserved renal hemodynamics (GFR, RBF), tubular reabsorption (Na, K, Cl, fluid, glucose, calcium, phosphate) and tubular secretion (PAH) at 1 day and 1 week after hemorrhage. Measurement of albuminuria and markers of kidney injury and inflammation (incl. urine NGAL to creatinine ratios and renal mRNA expression of KIM‐1, CCL2 and IL6) indicated that the level of injury or inflammation was not consistently increased among any of the 4 groups.ConclusionA single bolus infusion of ISO, VOL or HEX, dosed to acutely restore BP after a 25% blood loss in rats, preserved or maintained integrated kidney function to a similar extent, when assessed one day or one week later.Support or Funding InformationFresenius Kabi Deutschland GmbHThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Influence of Maternal High Fat Diet and Ozone Exposure on Serum Metabolomic Profiles in Juvenile Offspring

There is growing interest in understanding how maternal diet can affect the sensitivity of offspring to environmental exposures. Previous studies have demonstrated that adult offspring from dams given a high fat diet (HFD) prior to, during, and after pregnancy had elevated pulmonary responses to an acute ozone exposure. In this study, we examined the influence of maternal HFD on metabolic responses to ozone in male and female juvenile offspring. F0 female Long Evans rats began HFD (60% kcal from fat) or control diet (CD; 10.5% kcal from fat) at post‐natal day (PND) 30. Rats were bred on PND 75 and allowed to give birth. F1 litters were culled at PND 6 and offspring were weaned on PND 21. Offspring were maintained on respective HFD or CD until PND 30 when all groups were switched to CD. On PND 40, male and female offspring (n=8/group) were exposed to air or 0.8 ppm ozone for 5h. Immediately following exposure, animals were necropsied, serum was collected, and samples were subsequently assessed for changes in metabolite abundance using a metabolomic approach. Overall, analysis revealed significant changes in circulating metabolites due to sex, diet, and exposure. Maternal HFD increased serum microbiome‐associated histidine metabolites in male and tyrosine metabolites in female offspring, whereas selected free fatty acids were increased and phospholipids were decreased in both sexes. Furthermore, lower levels of 1,5‐anhydroglucitol were observed in all HFD groups regardless of sex or exposure. During hyperglycemic episodes, this metabolite is competitively inhibited by glucose for renal tubular reabsorption, thus decreases here may point towards development of insulin resistance in the offspring of mothers fed the HFD. Ozone exposure also had significant effects on serum metabolites. Decreases in biliverdin and bilirubin, heme catabolites with antioxidant properties, were detected in ozone‐exposed male and female offspring fed the CD but not the HFD, suggesting that the maternal diet may impact heme metabolism in offspring. Increases in free polyunsaturated fatty acids (PUFAs) were observed in ozone‐exposed male rats whereas in the female HFD ozone group, decreases in free PUFAs and monounsaturated fatty acids were apparent. Moreover, exposure to ozone led to increased levels of glucose in male rats regardless of maternal diet; however, in female offspring, pyruvate levels were elevated suggesting an increase in glucose utilization. This is supported by an ozone‐induced increase in the TCA cycle intermediates citrate and isocitrate in the female offspring of the HFD group. Collectively, the dataset suggest that ozone exposure elicits greater metabolic impact in juvenile female than male rats, and that maternal diet may further potentiate this effect. These results represent the basis to study the effects of maternal HFD on offspring sensitivity towards environmental factors and clearly suggest that susceptibility to ozone‐induced injury is sex‐dependent. (This abstract does not reflect US EPA Policy)Support or Funding InformationThis work was supported by US EPA funds.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Individualized treatment strategies for hyperuricemia informed by a semi-mechanistic exposure-response model of uric acid dynamics.

To provide insight into pharmacological treatment of hyperuricemia we developed a semi‐mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR,FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co‐administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure‐response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

SINGLE-NUCLEOTIDE POLYMORPHISMS OF CALCIUM-SENSING RECEPTOR ENCODING GENE ASSOCIATED WITH CALCIUM KIDNEY STONE DISEASE IN BABYLON PROVINCE

Objective: The calcium-sensing receptor (CASR) is a G-protein-coupled receptor that is mainly expressed in the parathyroid and the kidneys where it regulates parathyroid hormone secretion and renal tubular calcium reabsorption. Inactivating and activating CASR gene due to mutations severally caused hypercalcemia or hypocalcemia disorders. The aim of the study was to investigate the risk factor of CASR rs1801725 (Ala986Ser) patients with renal disease.Method: The blood samples were collected from 100 patients and divided into two groups, each one containing 50 samples; chronic kidney disease and end-stage renal disease, who admitted Merjan Teaching Hospital in Babylon Province, Iraq, from February to July 2016. In addition, healthy persons as a control group (50 samples). Genotyping of CASR single-nucleotide polymorphisms (SNP) was performed using a polymerase chain reaction technique, followed by single-strand conformation polymorphism. Accordingly, these DNA polymorphisms were confirmed using DNA sequencing.Results: The conformational haplotypes of CASR, exon7 NCBI Primer3plus reference were obtained in three patterns, including two, three, and four bands, due to the presence SNPs within the studied region. These SNPs leads to change three amino acid residues of CASR, including amino acid substitutions were Ala 128→ Ser 128, Leu 155→Tye 155, and Leu 156→ Ser 156 that may affect or modified the tertiary structure of the receptor, subsequently the function like the affinity to calcium ion may be effected.Conclusion: These results suggest that the variants of CASR SNP, namely, rs1801725 might be involved in susceptibility to kidney stone disease.

Hypertension and cardiometabolic disease.

Hypertension has a central role in cardiometabolic disease and is usually associated with metabolic disorders, such as insulin resistance, obesity, and dyslipidemia. Hyperinsulinemia may increase cardiovascular (CV) risk through its promotion of hypertension, which is possibly a result of chronic enhancement of sympathetic nervous system activity, stimulation of the renin-angiotensin-aldosterone system leading to increased renal tubular sodium reabsorption, modulating cation transport, or inducing vascular smooth muscle cell hypertrophy. The body mass index value is associated with hypertension, but additional analyses showed that the strongest link existed between visceral obesity and hypertension. In a cross-sectional study, we have already shown that pulse pressure (PP) amplification, heart rate (HR), and pulse valve velocity (PWV), but not augmentation index (Aix), are increased in patients with metabolic syndrome (MS). The basis of therapy for hypertension in MS lies in a changed way of life, involving caloric intake reduction, increased quality of food, increased physical activity, and medicamentous therapy. Such a therapy has a favorable impact not only on blood pressure (BP), but on all the components of MS, and is able to delay the onset of diabetes.

Genetic Causes of Rickets.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus.

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

Impact of Conventional Medical Therapy on Bone Mineral Density and Bone Turnover in Adult Patients with X-Linked Hypophosphatemia: A 6-Year Prospective Cohort Study.

X-linked hypophosphatemia (XLH) is a rare, inheritable disorder manifesting as rickets in children and osteomalacia in adults. While conventional medical treatment with oral phosphate and alfacalcidol is recommended in childhood, it is undecided whether adults should continue therapy. The aim of this 6-year prospective study was to determine the impact of conventional medical treatment on areal bone mineral density (aBMD), bone turnover markers (BTMs) and measures of calcium homeostasis in 27 adult patients with XLH, 11 of whom received medical treatment. Lumbar spine and total hip aBMD, as assessed by DXA, and biochemical measures of calcium, phosphate, PTH, 1,25 dihydroxyvitamin D2+3 (1,25(OH)2D), fibroblast growth factor 23 (FGF23), P1NP and CTX were measured at baseline and at follow-up. The renal tubular reabsorption of PO4 (TmPO4/GFR) was calculated at both time points. Multilevel mixed-effects linear regression models were used for analyses. During the study period, spine and hip aBMD did not change significantly between treated and non-treated XLH patients. There was a trend towards a decrease in calcium, phosphate and TmPO4/GFR in the treatment group (p=0.057, p=0.080 and p=0.063, respectively), whereas PTH, FGF23, 1,25(OH)2D and P1NP did not change significantly in either groups. However, CTX increased significantly in the treated compared to non-treated group (p=0.044). Continuing conventional medical therapy in adulthood, although associated with increased bone resorption, does not promote or prevent loss of bone mass as evidenced from the stable aBMD of the hip and spine in XLH patients.

Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Effects of voluntary exercise on blood pressure, angiotensin II, aldosterone, and renal function in two-kidney, one-clip hypertensive rats.

Spontaneous dynamic exercise promotes sympathoinhibition and decreases arterial pressure in two-kidney, one-clip (2K-1C) hypertensive rats. Renal sympathetic nerves stimulate renin secretion and increase renal tubular sodium reabsorption. We hypothesized that daily voluntary wheel running exercise by 2K-1C rats will decrease mean arterial pressure (MAP), plasma angiotensin II (Ang II), and aldosterone as well as normalize urinary sodium and potassium excretion independent of changes in glomerular filtration rate (GFR). Five-week-old male Sprague Dawley rats underwent sham clipping (Sham) or right renal artery clipping (2K-1C). Rats were randomized to standard caging (SED) or cages with running wheels (EX). After 12 weeks, rats were assigned to either collection of aortic blood for measurement of Ang II and aldosterone or assessment of inulin clearances and excretory function. Running distances were comparable in both EX groups. MAP was lower in 2K-1C EX vs 2K-1C SED rats (P<0.05). Plasma Ang II and aldosterone were significantly higher in 2K-1C SED rats and decreased in 2K-1C EX rats to levels similar to Sham SED or Sham EX rats. Clipped kidney weights were significantly lower in both 2K-1C groups, but GFR and urine flow rates were no different from right and left kidneys among the four groups. Total and fractional sodium excretion rates from the unclipped kidney of 2K-1C SED rats were higher vs either Sham group (P<0.05). Values in 2K-1C EX rats were similar to the Sham groups. Potassium excretion paralleled sodium excretion. These studies show that voluntary dynamic exercise in 2K-1C rats decreases plasma Ang II and aldosterone, which contribute to the lower arterial pressure without deleterious effects on GFR. The effects on sodium excretion underscore the impact of pressure natriuresis despite elevated plasma Ang II and aldosterone in sedentary 2K-1C rats. In contrast, potassium excretion is primarily regulated by circulating aldosterone and distal sodium delivery.

A Novel Multi-Epitope Vaccine Based on Urate Transporter 1 Alleviates Streptozotocin-Induced Diabetes by Producing Anti-URAT1 Antibody and an Immunomodulatory Effect in C57BL/6J Mice.

Hyperuricemia (HUA) is related to diabetes. Uric acid-induced inflammation and oxidative stress are risk factors for diabetes and its complications. Human urate transporter 1 (URAT1) regulates the renal tubular reabsorption of uric acid. IA-2(5)-P2-1, a potent immunogenic carrier designed by our laboratory, can induce high-titer specific antibodies when it carries a B cell epitope, such as B cell epitopes of DPP4 (Dipeptidyl peptidase-4), xanthine oxidase. In this report, we describe a novel multi-epitope vaccine composing a peptide of URAT1, an anti-diabetic B epitope of insulinoma antigen-2(IA-2) and a Th2 epitope (P2:IPALDSLTPANED) of P277 peptide in human heat shock protein 60 (HSP60). Immunization with the multi-epitope vaccine in streptozotocin-induced diabetes C57BL/6J mice successfully induced specific anti-URAT1 antibody, which inhibited URAT1 action and uric acid reabsorption, and increased pancreatic insulin level with a lower insulitis incidence. Vaccination with U-IA-2(5)-P2-1 (UIP-1) significantly reduced blood glucose and uric acid level, increased Th2 cytokines interleukin (IL)-10 and IL-4, and regulated immune reactions through a balanced Th1/Th2 ratio. These results demonstrate that the URAT1-based multi-epitope peptide vaccine may be a suitable therapeutic approach for diabetes and its complications.

Pleiotropic Actions of FGF23.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.

Multimodality Image-Guided Cryoablation for Inoperable Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a debilitating paraneoplastic condition caused by small phosphaturic mesenchymal tumors (PMTs) that secrete large amounts of the phosphate-regulating and vitamin D-regulating hormone, FGF23. Tumor removal results in cure. However, because of high perioperative comorbidity, either from tumor location or host factors, surgery is sometimes not an option. Tumor destruction via cryoablation may be an effective option for inoperable PMTs. Three subjects with a confirmed diagnosis of TIO were studied. All three underwent cryoablation of suspected PMTs rather than surgery due to significant medical comorbidities or challenging anatomical location. Subject 3 had tumor embolization 24 hours prior to cryoablation because of the size and hypervascularity of the tumor. The success of the tumor cryoablation was defined by normalization of serum phosphate and FGF23. Cryoablation resulted in a rapid decrease in plasma intact FGF23 by 24 hours postprocedure in all three subjects (0, 2, and 9 pg/mL, respectively) with normalization of blood phosphate by postprocedure day 3. Three-day renal tubular reabsorption of phosphate increased to 76%, 94%, and 95.2%, respectively; 1, 25(OH)2 vitamin D increased to 84, 138, and 196 pg/ml, respectively. All three had dramatic clinical improvement in pain and weakness. Two subjects tolerated the procedure well with no complications; one had significant prolonged procedure-related localized pain. Although surgery remains the treatment of choice, cryoablation may be an effective, less invasive, and safe treatment for patients with difficult to remove tumors or who are poor surgical candidates. © 2017 American Society for Bone and Mineral Research.

Tumour-induced osteomalacia

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.